Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. Tuberculosis is a respiratory transmitted disease affecting nearly 32% of the world's population, more than any other infectious disease. The mortality and spread of this disease has further been aggravated because of synergy of this disease with HIV. Approximately 50% of India's population is reported to be tuberculin test positive and one person dies from TB every minute.
Chemotherapy of tuberculosis started in early forties and since then a number of anti-tubercular agents have been discovered including para-aminosalicylic acid (PAS), isoniazid (INH), pyrazinamide (PZA), cycloserine, ethionamide, rifampicin (RMP), and ethambutol. Strategies have been devised to treat TB from time to time and current treatment involves a combination therapy that extends for months at a time, and the pharmacology of these treatment regimens can be complex. Moreover, a number of anti-TB drugs are found to be ineffective against the disease because of development of resistance strains.
The initial lack of understanding of drug action because of ignorance in the biochemistry of the Mycobacterium and the difficulty in manipulating M. tuberculosis had hindered efforts to define the mode of action of these agents. Based on the recent developments in evaluating the fine structure and biochemistry of Mycobacterium bacilli, it is observed that the cell wall of Mycobacterium plays a key role in growth and survival of Mycobacterium tuberculi (Mtb). The cell wall in M. tuberculosis being very complex and of very poor permeability, contributes significantly to the resistance against many therapeutic agents and for the long life in human lungs. [(a) Tam, P.-H.; Lowary, T. L., Curr. Opin. Chem. Biol. 2009, 13, 618-625; (b) P. J. Brennan, Tuberculosis, 2003, 83, 91-97; (c) M. Daffe and P. Draper, in Adv. Microb. Physiol. 1998, 131-203].
The major portion of the cell wall of Mtb is made up of the polysaccharides arabinogalactan (AG) and lipoarabinomannan (LAM). The AG and LAM polysaccharides are composed of arabinose and are synthesized inside the infected host cells. Arabinan component present in the polysaccharide contains approx 70 arabinofuranose residues. A key structural motif in this arabinan is the hexasaccharide, which is found at the non-reducing ends of both polymers. Mycobacterial viability is critically dependent upon its ability to produce both polysaccharides.
Since arabinose is foreign to the mammalian cells, the inhibition of the corresponding enzymes arabinosyltransferases (AraTs) play a critical role in mycobacterial cell wall biosynthesis and are considered as potential drug targets for the treatment of tuberculosis, especially multi-drug resistant forms of M. tuberculosis. Much of the research is now directed to the synthesis of natural products consisting of arabinofuranose rings as potential anti TB agents.
Article titled “Synthesis of octyl arabinofuranosides as substrates for mycobacterial arabinosyltransferases” by Jeongseok Han, Rajendrakumar Reddy et. al in Carbohydrate Research 338 (2003) 581-588, describes a panel of octyl oligosaccharides comprising of arabinofuranose rings. The process for glycosylation reactions involves coupling of octyl glycoside acceptors with the appropriate thioglycosides using N-iodosuccinimide and silver triflate activation. The synthesis disclosed provides substrates suitable for use in assays of mycobacterial arabinosyl transferases.
Article titled “Synthesis of deoxygenated all α(1→5)-linked arabinofuranose disaccharides as substrates and inhibitors of arabinosyltransferases of Mycobacterium tuberculosis” by Ashish K. Pathaka, Vibha Pathaka et al in Bioorganic & Medicinal Chemistry Volume 17, Issue 2, 15 Jan. 2009, Pages 872-881 discloses the synthesis and acceptor/inhibitory activity of Araf α(1→5) Araf disaccharides possessing deoxygenation at the reducing sugar of the disaccharide. Deoxygenation at either the C-2 or C-3 position of Araf was achieved via a free radical procedure using xanthate derivatives of the hydroxyl group (shown in figure below). The α(1→5)-linked disaccharides were produced by coupling n-octyl α-Araf 2-/3-deoxy, 2-fluoro glycosyl acceptors with an Araf thioglycosyl donor. The target disaccharides were tested in a cell free mycobacterial AraTs assay as well as an in vitro assay against MTB H37Ra and M. avium complex strains.

Article titled “Synthesis and Conformational Investigation of Methyl 4a-Carba-D-arabinofuranosides” by Christopher S. Callam and Todd L. Lowary J. Org. Chem. 2001, 66, 8961-8972 discloses the synthesis of carbasugar analogues of methyl α-D-arabinofuranoside and methyl β-D-arabinofuranoside (3 and 4) in identifying inhibitors of the arabinosyltransferases that are involved in the assembly of mycobacterial cell wall polysaccharides. Starting from D-mannose, the targets are obtained via a route in which the key steps are (i) a ring-closing metathesis and (ii) a subsequent stereoselective hydrogenation. The article further states that the route can also be applied to the preparation of other carbafuranoses through substitution of D-mannose with other pyranose sugars.

Article titled “Stereoselective synthesis of β-arabino glycosyl sulfones as potential inhibitors of mycobacterial Cell wall biosynthesis” by Benjamin Ayers, Hilary Long et. al in Carbohydrate Research Volume 344, Issue 6, 21 Apr. 2009, Pages 739-746, describes synthesis of a series of β-arabino glycosyl sulfones with varying alkyl chain lengths in a stereoselective fashion as putative mimics of decaprenolphosphoarabinose (DPA), and as potential inhibitors of mycobacterial cell wall biosynthesis.

Article titled “Synthesis of methyl 5-S-alkyl-5-thio-d-arabinofuranosides and evaluation of their anti-mycobacterial activity” by Aditya K. Sankia, Julie Boucaua et al. in Bioorganic & Medicinal Chemistry, Volume 16, Issue 10, 15 May 2008, Pages 5672-5682, discloses synthesis of methyl 5-S-alkyl-5-thio-d-arabinofuranoside analogues as potential inhibitors of mycobacterial antigen 85 complex. The antigen 85 (ag85) complex which is a family of mycolyl transferases is involved in the synthesis of trehalose-6,6′-dimycolate and the mycolated hexasaccharide motif found at the terminus of the arabinogalactan in mycobacterium. Two of the compounds, 5-S-octyl-5-thio-α-D-arabinofuranoside (8) and 5-S-octyl-5-thio-β-d-arabinofuranoside (11) are disclosed to exhibit potential antibacterial activity against Mycobacterium smegmatis ATCC 14468.

Further studies revealed that the enzyme arabinosyl transferases (AraT) involved in biosynthesis of AG and LAM utilize a single substrate i.e. β-decaprenyl-D-arabinofuranosyldiphosphate. This prompted a search for the mimics of the β-DPA as potential inhibitors for AraTs inter alia new anti-tubercular drug candidates.
